Epidemiological studies suggest an inverse correlation between soyfood consumption and human cancer mortality. Laboratory studies indicate that soy diets also inhibit experimentally induced animal tumors. Although most studies attribute the anticarcinogenic effect of soybeans to the protease inhibitors, increasing evidence suggests that isoflavones, non- protein components richly present in soybeans, may also play important roles. Genistein, one of the major soybean isoflavones, has been shown to inhibit tyrosine protein kinase (TPK), DNA topoisomerase II (Topo II), and ribosomal S6 kinase (RS6K), suppress tumor cell growth, and induce differentiation of several malignant cell lines. Our preliminary studies have shown that genistein significantly prevents 7,12- dimethylbenz[a]anthracene (DMBA)-DNA adduct formation and inhibits 12-O- tetradecanoyl phorbol-13-acetate (TPA)-induced H2O2 formation, inflammatory responses, and proto-oncogene expression in vivo. However, whether genistein modifies chemical carcinogenesis in vivo remains unclear. This proposal is designed to test the hypothesis that genistein inhibits oxidative DNA damage induced by carcinogenic agents and further modifies the initiational, promotional, and progressional processes of chemical carcinogenesis. The overall objective is to determine if genistein modifies the initiation- and promotion-related events and subsequently inhibits skin tumor formation in vivo. The initial aim of the project is to determine if topical application of genistein modifies the initiation- and promotion-related events with an emphasis on oxidative DNA damage. The second aim is to determine if topical application of genistein affects initiation, promotion and/or progression of multistage skin. carcinogenesis. The third aim is to examine if topical application of genistein inhibits the DMBA-induced complete carcinogenesis. Finally, we will determine if dietary administration of genistein modulates these carcinogenic processes in the multistage carcinogenesis model. If, in fact, genistein has anticarcinogenic effects, an elucidation of the mechanisms of genistein's action will contribute to application of this soybean isoflavone in prevention and/or therapy of human cancers.